Prevention effect of orally active heparin conjugate on cancer-associated thrombosis.


Thrombogenesis is a major cause of morbidity and mortality in cancer patients. Prophylaxis with low-molecular-weight heparin (LMWH) is recommended for cancer patients, but requires non-parenteral delivery methods for long-term treatments. In this study, we sought to generate a new oligomeric-bile acid conjugate of LMWH that can be used for oral delivery. We first synthesized a tetramer of deoxycholic acid (tetraDOCA), which was site-specifically conjugated at the end saccharide of LMWH. When LMWH-tetraDOCA conjugate (LHe-tetraD) was orally administered at a dose of 5 mg/kg in ICR mice, the maximum anti-factor Xa level was increased up to 0.62±0.05 IU/mL without any evidence of liver toxicity, gastrointestinal damage, or thrombocytopenia. The cancer-associated thrombosis was induced in tumor-bearing mice by local heat application, and the fibrin deposition in tumors was evaluated. The oral administration of LHe-tetraD (either a single dose or multiple daily doses for up to 10 days) in mice substantially abolished the coagulation-dependent tropism of fibrinogen in the heated tumors and significantly decreased hemorrhage, compared to the mice treated with saline or subcutaneous injection of LMWH. Thus, the anticoagulation effect of oral LHe-tetraD invokes the benefits of oral delivery and promises to provide an effective and convenient treatment for cancer patients at risk of thrombosis.

DOI: 10.1016/j.jconrel.2014.05.027

Cite this paper

@article{AlHilal2014PreventionEO, title={Prevention effect of orally active heparin conjugate on cancer-associated thrombosis.}, author={Taslim Ahmed Al-Hilal and Farzana Alam and Jin Woo Park and Kwangmeyung Kim and Ick Chan Kwon and Gyu Ha Ryu and Youngro Byun}, journal={Journal of controlled release : official journal of the Controlled Release Society}, year={2014}, volume={195}, pages={155-61} }